The present invention relates to methods of treating anxiety and depression using R-6-hydroxy-buspirone and pharmaceutical compositions containing R-6-hydroxy-buspirone.
Buspirone, chemically: 8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl-8-azaspiro(4,5)-decane-7,9-dione, is approved for the treatment of anxiety disorders and depression by the United States Food and Drug Administration. It is available under the trade name BUSPAR(copyright) from Bristol-Myers Squibb Company.
Studies have shown that buspirone is extensively metabolized in the body. (See, for example, Mayol, et al., Clin. Pharmacol. Ther., 37, p. 210, 1985). One of the metabolites is 6-hydroxy-8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl-8-azaspiro(4,5)-decane-7,9-dione having Formula I. This metabolite is also known as BMS 28674, BMS 442608, or 
as 6-hydroxy-buspirone. This compound is believed to be the active metabolite of buspirone and its use in treating anxiety disorders and depression is disclosed in U.S. Pat. No. 6,150,365. The specific stereochemistry of 6-hydroxy-buspirone has not been described previously. Neither racemic 6-hydroxy-buspirone nor its enantiomers are commercially available at the present time.
Preclinical studies demonstrate that 6-hydroxy-buspirone, like buspirone, demonstrates a strong affinity for the human 5-HT1A receptor. In functional testing, 6-hydroxy-buspirone produced a dose-dependent anxiolytic response in the rat pup ultrasonic vocalization test, a sensitive method for assessment of anxiolytic and anxiogenic effects (Winslow and Insel, 1991, Psychopharmacology, 105:513-520).
Clinical studies in volunteers orally dosed with buspirone demonstrate that 6-hydroxy-buspirone blood plasma levels were not only 30 to 40 times higher but were sustained compared to buspirone blood plasma levels. The time course of 6-hydroxy-buspirone blood plasma levels, unlike buspirone blood plasma levels, correlate more closely with the sustained anxiolytic effect seen following once or twice a day oral dosing with buspirone.
Although buspirone is an effective treatment for anxiety disorders and depression symptomatology in a significant number of patients treated, about a third of patients get little to no relief from their anxiety and responders often require a week or more of buspirone treatment before experiencing relief from their anxiety symptomatology. Further, certain adverse effects are reported across the patient population. The most commonly observed adverse effects associated with the use of buspirone include dizziness, nausea, headache, nervousness, lightheadedness, and excitement. Also, since buspirone can bind to central dopamine receptors, concern has been raised about its potential to cause unwanted changes in dopamine-mediated neurological functions and a syndrome of restlessness, appearing shortly after initiation of oral buspirone treatment, has been reported in small numbers of patients. While buspirone lacks the prominent sedative effects seen in more typical anxiolytics such as the benzodiazepines, patients are nonetheless advised against operating potentially dangerous machinery until they experience how they are affected by buspirone.
It can be seen that it is desirable to find a medicament with buspirone""s advantages but which demonstrates more robust anxiolytic potency with a lack of the above described adverse effects.
Formation of 6-hydroxy-buspirone occurs in the liver by action of enzymes of the P450 system, specifically CYP3A4. Many substances such as grapefruit juice and certain other drugs; e.g. erythromycin, ketoconazole, cimetidine, etc., are inhibitors of the CYP3A4 isozyme and may interfere with the formation of this active metabolite from buspirone. For this reason it would be desirable to find a compound with the advantages of buspirone but without the drugxe2x80x94drug interactions when coadministered with agents affecting the activity level of the CYP3A4 isozyme.
It has now been discovered that the R-isomer of 6-hydroxy-buspirone is an effective treatment for anxiety disorders and depression which should not give rise to the adverse effects associated with buspirone, as well as having an advantage in specificity over racemic 6-hydroxy-buspirone. Therefore, in one aspect, the present invention relates to a method of treating anxiety disorders and depression, comprising administration to a person in need of such therapy a therapeutically effective amount of R-6-hydroxy-buspirone or a pharmaceutically acceptable salt thereof.
It has also been discovered that the R-isomer of 6-hydroxy-buspirone is useful in treating a number of other clinical disorders. Specifically, the present invention relates to methods of treating the following: extrapyramidal motor disorders; panic disorders such as panic attacks; agoraphobia, and phobic anxiety; short-term memory deficit; alcohol abuse and alcoholism symptomatology; nicotine dependence; drug addiction; eating disorders; post traumatic stress disorder; sleep-related respiratory disorders such as sleep apnea and sudden infant death syndrome; childhood autism; pre-menstrual syndrome; sexual dysfunction; agitation; hostility; obsessive-compulsive disorder; nausea and vomiting; incontinence; and acute and chronic pain.
Yet another aspect of the present invention goes to pharmaceutical compositions comprising R-6-hydroxy-buspirone and their administration for treatment of clinical disorders.
And in a further aspect, the invention relates to R-6-hydroxy-buspirone itself, substantially free of the R-enantiomer, or a pharmaceutically acceptable salt thereof.
The active compound of the methods and compositions of the present invention is R-6-hydroxy-buspirone. The compound contains a chiral center that gives rise to the respective R- and S-spatial configurations. Neither enantiomer has been described in the literature. The structure of R-6-hydroxy-buspirone is shown in Formula II. 
The R-6-hydroxy-buspirone utilized for the methods and compositions of the present invention is substantially free of the S-stereoisomer of 6-hydroxy-buspirone, S-6-hydroxy-buspirone. The term xe2x80x9csubstantially free of the S-stereoisomerxe2x80x9d as used herein means that the compound and compositions of the present invention contain a significantly greater proportion of the R-isomer of 6-hydroxy-buspirone in relation to the S-isomer of 6-hydroxy-buspirone. In a preferred embodiment of the present invention, the compositions contain at least 90% by weight of R-6-hydroxy-buspirone and 10% by weight or less of S-6-hydroxy-buspirone. More preferably, the compositions contain at least 98% by weight of R-6-hydroxy-buspirone and 2% by weight or less of S-6-hydroxy-buspirone, and in this case, the term xe2x80x9csubstantially free of the S-isomerxe2x80x9d means that the compositions contain at least 98% by weight of R-6-hydroxy-buspirone and 2% by weight or less of S-6-hydroxy-buspirone. These percentages are based upon the total amount of 6-hydroxy-buspirone in the composition. The terms xe2x80x9csubstantially optically pure R-isomer of 6-hydroxy-buspironexe2x80x9d or xe2x80x9csubstantially optically pure S-6-hydroxy-buspironexe2x80x9d and xe2x80x9coptically pure R-isomer of 6-hydroxy-buspironexe2x80x9d and xe2x80x9coptically pure S-6-hydroxy-buspironexe2x80x9d are also encompassed by the above-described amounts.
The present invention also encompasses a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of R-6-hydroxy-buspirone or a pharmaceutically acceptable acid addition salt and/or hydrate thereof. Pharmaceutically acceptable acid addition salts of R-6-hydroxy-buspirone are those in which the anion does not contribute significantly to toxicity or pharmacologic activity of the base form of R-6-hydroxy-buspirone.
Acid addition salts are obtained either by reaction of R-6-hydroxy-buspirone with an organic or inorganic acid, preferably by contact in solution, or by any of the standard methods detailed in the literature and available to any practitioner skilled in the art. Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, pamoic acid, and the like; useful inorganic acids are hydrohalide acids such as HCl, HBr, Hl; sulfuric acid; phosphoric acid; and the like.
Any suitable route of administration may be employed for providing the patient with an effective dosage of R-6-hydroxy-buspirone. For example, oral, rectal, parenteral (including subcutaneous, intramuscular, and intravenous) routes may be employed. Sublingual, buccal, transdermal and transnasal routes of administration are also contemplated. Dosage forms include tablets, troches, dispersions, nasal sprays, suspensions, solutions, capsules and patches.
Compositions suitable for oral, buccal, sublingual, transdermal, transnasal, and parenteral administration are encompassed by the present invention. A preferred route of administration is oral. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient, R-6-hydroxy-buspirone, or a pharmaceutically acceptable salt thereof.
R-6-hydroxy-buspirone may be prepared utilizing methods of synthesis and enantiomeric separation known to one skilled in the art. One method of preparation (Scheme 1) utilizes buspirone as a starting material to produce racemic 6-hydroxy-buspirone that is separated into the two enantiomers by chiral chromatographic techniques. 
An improved one-step synthesis of racemic 6-hydroxy-buspirone is set forth in Scheme 2. Again, enantiomeric separation provides R-6-hydroxy-buspirone. 
The present invention encompasses R-6-hydroxy-buspirone, substantially free of S-6-hydroxy-buspirone. The R- and S-isomers of hydroxy-buspirone may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting an enantiomer to the other by asymmetric transformation.
R-6-hydroxy-buspirone is believed to offer improved therapeutic treatment to sufferers of a variety of clinical disorders. Preclinical testing utilized ultrasonic vocalizations emitted by rat pups following isolation from their mother and littermates and subjected to a variety of environmental stimula (e.g., cold temperature). Statistically significant anxiolytic activity was demonstrated for both racemic 6-hydroxy-buspirone and R-6-hydroxy-buspirone at dose levels of 0.3 and 1 mg/kg s.c. However, animal movement, measured by crossing grid boundary lines, appeared to be reduced for the animals dosed with racemic 6-hydroxy-buspirone compared to the animals dosed with the single enantiomer. This difference between drug groups and animal movement suggests that R-hydroxy-buspirone may possess less side-effect potential than the racemate. Receptor binding studies for the 6-hydroxy-buspirone enantiomers indicate that the R-enantiomer possesses greater receptor specificity than the S-isomer (see Table 1).
These data support the conclusion that adverse effects from racemic 6-hydroxy-buspirone such as sedation, dizziness, malaise, etc. that act to inhibit animal locomotion, are absent or significantly lessened in R-6-hydroxy-buspirone.
Therefore, administration of R-6-hydroxy-buspirone should result in fewer adverse effects compared with the administration of the racemic mixture. One or more of the following adverse effects of the racemate may be reduced or avoided by administration of the R-enantiomer of 6-hydroxy-buspirone: dizziness, nausea, headache, nervousness, lightheadedness, excitement, and sedation.
Administration of R-6-hydroxy-buspirone pharmaceutical formulations to patients for the treatment of various clinical disorders is a major aspect of the present invention. The clinical disorders to be treated by administration of R-6-hydroxy-buspirone comprise the following: anxiety disorders; depression; anxiety mixed with depression; panic disorders such as panic attacks, agoraphobia, and phobic anxiety; extrapyramidal motor disorders; short-term memory deficit; alcohol abuse and alcoholism symptomatology; nicotine dependence; drug addiction; eating disorders; post traumatic stress disorder; sleep-related respiratory disorders such as sleep apnea and sudden infant death syndrome; pre-menstrual syndrome; childhood autism; agitation; hostility; obsessive-compulsive disorder; sexual dysfunction; incontinence; nausea and vomiting; and acute and chronic pain.
The magnitude of prophylactic or therapeutic dose of R-6-hydroxy-buspirone will vary with the nature and severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient. In general, the total daily dose ranges from about 5 mg per day to about 100 mg per day, preferably about 30 mg per day to about 60 mg per day, in single or divided doses. It is further recommended that children, patients over 65 years old, and those with impaired renal or hepatic function, initially receive low doses and that the dosage may be increased by titration based on individual responses and blood levels. It may be necessary to use dosages outside these ranges in some cases, as will be apparent to those in the art. Further, it is noted that the clinician or treating physician knows how and when to interrupt, adjust or terminate therapy in conjunction with the individual patient""s response.
The compositions of the present invention may also include a pharmaceutically acceptable carrier. The carrier may take a wide variety of forms, depending on the route of administration desired; for example, oral and parenteral (including intravenous). In preparing the composition for an oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents in the case of oral liquid preparation, including suspension, elixirs and solutions. Carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents may be used in the case of oral solid preparations such as powders, capsules and caplets, with the solid oral preparation being preferred over the liquid preparations. Preferred solid oral preparations are tablets or capsules, because of their ease of administration. If desired, tablets may be coated by a standard aqueous or nonaqueous techniques. Oral and parenteral sustained release dosage forms may also be used.
Oral syrups, a well as other oral liquid formulations, are well known to those skilled in the art, and general methods for preparing them are found in any standard pharmacy school textbook, for example Remington: The Science and Practice of Pharmacy. Chapter 86 of the 19th edition of Remington entitled xe2x80x9cSolutions, Emulsions, Suspensions and Extractsxe2x80x9d describes in complete detail the preparation of syrups (pages 1503-1505) and other oral liquids. Similarly, sustained release formulation is well known in the art, and Chapter 94 of the same reference, entitled xe2x80x9cSustained-Release Drug Delivery Systems,xe2x80x9d describes the more common types of oral and parenteral sustained-release dosage forms (pages 1660-1675). The relevant disclosure, Chapters 84 and 96, is incorporated herein by reference. Because they reduce peak plasma concentrations, as compared to conventional oral dosage forms, controlled-release dosage forms are particularly useful for providing a therapeutic plasma concentration of R-hydroxy-buspirone while avoiding the side effects associated with high peak plasma concentrations that occur with conventional dosage forms.
The compound whose use constitutes this invention and its method of preparation will appear more fully in light of the following examples which are given for the purpose of illustration only and are not to be construed as limiting the invention in sphere or scope.